Role of TCA cycle Truncation in Cancer Cell Energeticsabap.co.in/sites/default/files/Paper-11_17.pdfThe question arises, how TCA cycle gets truncated in a cancerous cell, which has

Current Trends in Biotechnology and PharmacyVol. 8 (4) 428-438 October 2014, ISSN 0973-8916 (Print), 2230-7303 (Online)

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AbstractContinuously dividing cancerous cell

requires duplication of its genome and othercellular building blocks before every cell division.This increased demand for amino acids,nucleotides and fatty acids, require readjustmentof metabolic pathways, specially glycolysis andTCA cycle, to divert intermediates of these seriesof reactions from energy generating process(OXPHOS) to synthesis of cellularmacromolecule building blocks. This alteredcellular metabolism has been observed as earlyas 1926. Otto Warburg observed aerobicglycolysis and proposed defective mitochondriaas a cause of cancer. Since then, ‘Warburg effect’has become a hallmark of cancer detection bypositron emission tomography (PET) and is nowbeing perused for designing of novel anticancerdrug targeting enzymes like PKM2. However,since beginning, Warburg hypothesis ofnonfunctional mitochondria has been questioned.Now it is clear that cancerous cell has intact andfunctional mitochondria, moreover reverse.Warburg effect has proposed a nonfunctionalmitochondria in stromal tissue and with functionalOXPHOS system for ATP synthesis in cancerouscells. These two hypotheses of Warburg andreverse Warburg show two extremes one relyingalmost completely on aerobic glycolysis andanother on OXPHOS for ATP synthesis incancerous cell, but both of them fail to explainhow cell readjusts to meet increased demand forATP synthesis as well as cellular building blockssimultaneously, from the intermediates of

glycolysis and TCA cycle. In the presenthypothesis, we present how truncation of TCAcycle can increase rate of synthesis of aminoacids and simultaneously TCA cycle getscompleted to generate NADH and FADH2.Oncomine database analysis further showsupregulation of ATP synthase genes andindicative of increased OXPHOS I cancerouscell. In this background, we propose thatcancerous cell utilizes both aerobic glycolysis andOXPHOS, for synthesis of ATP and to meetincreased requirement of proteins, nucleic acidsand fatty acids.

Key words: Metabolic rearrangement, oncogenomics, oncogenic mutations, TCA cycle, ROS

IntroductionA common feature across most of

cancer types is increased glucose uptake andutilization. In contrast to normal cells, cancerouscell convert glucose to lactate even underaerobic conditions (1). Direct relationshipbetween malignant transformation and increasedglucose consumption has been nicelydemonstrated by increased glucose transportrate in cancer cell lines. This fact is widelyexploited for detection of cancer by 18F-deoxyglucose positron emission tomography(FDG-PET) (2, 3). Warburg proposed thataerobic glycolysis in cancer is the result ofdefective mitochondria (4-7) which leads to failureof energy generation by oxidativephosphorylation. The irrefutable facts that (i)

Role of TCA cycle Truncation in Cancer Cell Energetics

Vikrant Nain, Richa Buddham, Rekha Puria and Shakti Sahi *

School of Biotechnology, Gautam Buddha University, Greater Noida -201312, India*For Correspondence – [email protected]

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cancer cells consume more glucose incomparison to normal cell, (ii) secrete highconcentration of lactate and (iii) whensupplemented with radio labeled glucose ascarbon source most of the radioactivity is tracedto lactate rather than tricarboxylic acid cycle (TCAcycle) intermediates supports ‘Warburg Effect’.The adoption of an inefficient system of energygeneration (2 ATP vs 36 ATP) in highlyproliferating cancerous cells is an enigma sincelong. However, the existence of inefficient aerobicglycolysis in high energy demanding tissues(skeletal muscle), brain and rapidly dividing cellscorroborates this inefficient aerobic glycolysis inactively proliferating cancerous cells (8, 9).

Warburg’s hypothesis does not fullyjustify the growth behavior of cancer cells for e.g.,there is not much reduction in oxygenconsumption in cancerous cells. Further researchover the years has clearly revealed thatmitochondria in cancerous cells are intact andcancerous cell utilizes high dose of glutamine inaddition to glucose (10-12).The major challengeto this theory has come in the last five years,when one research group showed thatmitochondrial dysfunction with non-functionalOXPHOS and activated aerobic glycolysis is infact observed in the stromal tissue surroundingthe cancerous cells but not in cancerous cellsas proposed by Warburg (13). In this newhypothesis termed as ‘Reverse Warburg’ it isreported that mitophagy induces autophagy instromal tissue followed by the nutrienttransportation from the stromal cells to cancerouscells (14-16). In this model, cancerous cells giveautophagy signals to stromal cells and stromalcells provide nutrients to parasitic cancerouscells. Using various localization and functionalassays, intact mitochondrial membrane andvarious functional enzymes from glycolysis, TCAcycle and ETC chain have been shown (17).According to ‘Reverse Warburg’ hypothesis,FDG-PET actually detects accumulation ofradioactivity in stromal tissue, not in cancerouscells (14). These new findings have ultimatelylead to ‘neo-Warburg’ hypothesis, which

suggests that entry of glutamine in TCA cyclethrough alpha-ketoglutarate provides the muchneeded metabolic intermediates for biosynthesisof amino acids, nucleic acids and fatty acids (18).However, it is still assumed by proponents of‘Warburg’ hypothesis that in a cancerous cellmost of the energy comes from aerobicglycolysis. Thus, these two hypothesis depict twoextremes- one the ‘Warburg’, shows reliance ofcancerous cells on aerobic glycolysis and anotherthe ‘Reverse Warburg’ relies entirely onOXPHOS and supply of nutrients fromsurrounding cancer cell microenvironment.

Cancer cell metabolism has beenrecently extensively reviewed, emphasizing onmutations and oncogenic signaling (19),OXPHOS in cancerous cells (20), aerobicglycolysis as drug target (21, 22), decouplingglycolysis and TCA cycle (23), regulation ofdifferent biochemical pathways (24), extrametabolic roles of TCA cycle metabolites (25) andsignaling and communications with stromal cells(26). This review primarily summarizes variousmetabolic rearrangements in TCA cycle that areacquired to support the demand of energy(through OXPHOS and aerobic glycolysis) andsynthesis of macromolecules in growingcancerous cells. Inferences from literaturesuggest that aerobic glycolysis and truncation ofTCA cycle due to various physiological andgenetic factors support increased biosynthesisof cellular building blocks. Truncated TCA cycleis compensated by activation of variousalternative carbon (glutamate) utilizationpathways and helps completion of truncated TCAcycle and generation of FADH

2 and NADPH

2 for

synthesis of ATP through OXPHOS. Variousstructural adaptations in mitochondria, perhapsto incorporate more of ATP synthase, furthersupport active participation of both aerobicglycolysis and TCA in tumorigenesis.

Truncation of TCA cycle and switch tomultiple carbon sources in cancerous cells :The fact that continuous proliferation ofcancerous cells (or cell lines) requires supply ofglutamine (in addition to glucose) is widely

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accepted by proponents of both ‘Warburg’ as wellas ‘Reverse Warburg’ hypothesis. Probably theparallel consumption of two carbon sourcescomply with enhanced energy requirements andscale up synthesis of metabolic intermediatesrequired for cell duplication. However, switch overto glutamate as carbon source provides achallenge for the cell. In a cell, glutamate to alpha-ketoglutarate conversion is a nearthermodynamic equilibrium reaction, the netreaction can move either in or out of the Krebs’scycle, depending on the relative concentrationsof the two on each side of the chemical equation(cataplerotic or anaplerotic) (27). Therefore, aslong as enough glucose derived alpha-ketoglutarate is getting synthesized, glutamatecannot get utilized in the TCA cycle. Thus, inorder to utilize glutamate in TCA cycle, synthesisof alpha- ketoglutarate from glucose derivedcarbon must get reduced/ stopped. Thistruncated TCA cycle actually leads to secretionof accumulated citrate out of mitochondria thatgets utilized in nitrogen metabolism of cell. Thisalso explains the observed high level of citratesecreted from mitochondria to cytosol (28) andaerobic glycolysis in cancers (12).

The question arises, how TCA cycle getstruncated in a cancerous cell, which has beenfollowing normal series of biochemical reactionsfrom glycolysis, TCA cycle to ETC for energyproduction, before becoming cancerous?Apparently, the synthesis of alpha-ketoglutaratecould be reduced or stopped either by inhibitionor mutation in key enzyme like aconitase, iso-citrate dehydrogenase working upstream toalpha-ketoglutarate in TCA cycle. Furtherpyruvate kinase catalyzing last and irreversiblestep of glycolysis can truncate TCA cycle bylimiting the supply of pyruvate (29) (Figure 1).

Pyruvate Kinase : Pyruvate kinase is a keyenzyme that can truncate TCA cycle just at theentry point of pyruvate. Reduced pyruvate kinaseactivity enables the upstream glycolyticintermediates to accumulate and contribute tothe shift of metabolism towards the anabolicphase for synthesis of amino acids and

nucleotides. Cancer cells meet this increaseddemand by predominantly using PKM2, anisoform of pyruvate kinase, as its activity can bedynamically regulated between the less activePKM2 dimer and the highly active PKM2 tetramer(29, 30). PKM2 activity is allosterically regulatedby serine which is synthesized from 3-phosphoglycerate, a glycolytic intermediate (31).Availability of serine activates human PKM2 whiledeprivation reduces its activity significantly (31).Thus, in such scenario, it seems that whendemand of amino acids is more for proteinsynthesis, serine level gets depleted and inabsence of activator serine, PKM2 fails toproduce enough pyruvate to feed TCA cycle forenergy production as well as for synthesis ofother amino acids and fatty acids, starting fromTCA intermediates (Figure 1 A). In case of PKM2inhibition, conversion of glutamate to alpha-ketoglutarate not only complete the TCA cycleby subsequent conversion to succinate andfumarate but also get converted to citrate throughcarboxylation reaction (32).

Aconitase : Aconitase is another key enzymethat has potential to truncate TCA cycle, beforesynthesis of alpha-ketoglutarate. Aconitaseenzyme that catalyses the stereo-specificisomerization of citrate to isocitrate is sensitiveto inhibition by reactive oxygen species (ROS).Increase in ROS in cancerous cell is well known(33, 34) an its inhibition results in truncation ofTCA cycle at just before entry point of glutamate(Figure 1B). This inhibition of aconitase by ROSand subsequent truncation of TCA cycle is alsoapparent in diabetic neuropathy (35). Apparently,the TCA cycle truncated either by inhibition ofaconitase or PKM2 results in decreased alpha-ketoglutarate level. This triggers the activationof an anaplerotic conversion of glutamate toalpha-ketoglutarate and accumulation of variousintermediates of TCA cycle. Subsequently, theseget utilized in biosynthesis of fatty acids,nucleotides and amino acids. In fact, this increasein concentration of TCA metabolites and aminoacid biosynthesis has been observed in aconitasemutant in Arabidopsis (36).



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Isocitrate Dehydrogenase : Isocitratedehydrogenase (IDH) is another enzyme of TCAcycle that has potential to play key role inremodeling TCA cycle in cancerous cells. It is areversible enzyme that catalyzes the NADP+-dependent oxidative decarboxylation of isocitrate(ICT) to alpha-ketoglutarate and the NADPH/CO

2-dependent reductive carboxylation of alpha-

ketoglutarate to ICT. In World HealthOrganization grades II–IV gliomas, frequent (~70-80%) mutations have been reported in NADP+-dependent isocitrate dehydrogenases 1 and 2(IDH1 and IDH2) (37). IDH1 and IDH2 withcancer-associated mutations at the active siteare unable to carry out the reductive

carboxylation of alpha-ketoglutarate (38-40).These mutants are also defective in ICTdecarboxylation and converted alpha-ketoglutarate to 2-hydroxyglutarate using NADPH(38, 39). However, such mutations in IDH3 arenot generally present, even in grade II-III gliomasand secondary glioblastomas where IDH1 andIDH2 mutations are frequent (41). Thesemutations in cytosolic IDH1 have probableadvantage in blocking synthesis of glutamine,which helps cancerous cell from overcoming theproblem of glutamine synthesis and utilizationloop. One possible reason why mutations areabsent in mitochondrial IDH3, while they are sofrequent in IDH1 and IDH2 is that, these



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Fig. 1. Truncation of TCA cycle by inhibition/mutationof different enzymes A. Inhibition of PKM2 in absenceof serine leads to accumulation of glycolyticintermediates, while TCA cycle components arepredominantly synthesized from glutamine carbon,B. Inhibition of aconitase by ROS leads to truncationof TCA cycle, leading to aerobic glycolysis withcompletion of TCA cycle through anapleroticconversion of glutamate to alpha ketoglutarate andC. Inhibition of succinate dehydrogenase andfumarate hydratase further leads to truncation of TCAcycle that can be completed through anotheranaplerotic pyruvate to oxaloacetate conversion.

mutations abolish the carboxylic synthesis ofisocitrate from alpha- ketoglutarate. Thereby ina situation when enough glucose carbon is notavailable for citrate mediated synthesis ofrequired amino acids, IDH3 can convertglutamate to citrate and contribute in biosynthesisof required compounds. Hence, any mutation inIDH3 can be lethal to cancerous cell and not getfixed in progressive cancer.

Succinate dehydrogenase : Succinatedehydrogenase (SDH) and fumarate hydratase(FH) are other enzymes that link TCA cycle tonitrogen metabolism and their dysfunction hasbeen implicated in tumorigenesis. Moreover,

accumulated succinate and fumarate in responseto SDH and FH dysfunction get secreted tocytosol and there they inhibit a family of prolylhydroxylase enzymes that possibly play a role intumor maintenance by making the affected cellsresistant to certain apoptotic signals (42).However, truncation of TCA cycle at this step canprevent synthesis of oxaloacetate that is essentialfor synthesis of aspartate. Providentially, anotheranaplerotic reaction can generate oxaloacetatefrom pyruvate (Figure 1C). These observationsclearly indicate that although almost all steps ofTCA cycle are completed but key enzymes areeither down regulated or get mutated (possiblein advance stage of cancer) to modify the TCA


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cycle for accumulation of intermediates requiredfor synthesis of different amino acids, nucleic andfatty acids. The remaining steps of truncated TCAcycle further get completed using alternatecarbon source from the surrounding stromal cells.Intriguingly, in diabetic neuropathy nerve cellsalso show truncation of TCA cycle but are notable to sustain themselves as they lack glutaminefrom surroundings to fuel their energy demandunlike cancerous cells that have a surroundingstromal tissue to fuel TCA cycle throughglutamate and other metabolites (16, 35). Thus,absolute dependence of cancerous cell onglutamate is for efficient energy production andmacromolecule synthesis through multiplecarbon sources. Moreover, it has been illustratedin case of HeLa cells that glutamate generatesenergy as well as macromolecules by aerobicoxidation (10).

Structural adaptations in cancerous cellmitochondria for sustaining oxidativephosphorylation : Structural changes inmitochondria of various cancer cell types havebeen observed e.g., an increase in mitochondrialmass has been shown (13). Further elongationof mitochondria has been implicated inadaptations to nutrient scarcity and escapingautophagy, in different diseases and growthconditions (43). It seems that these mitochondrialstructural changes are made to maximize theutilization of available truncated TCA componentsfor growth of cancerous cells. An alteration inmitochondrial membrane may be to allowinsertion of more number of ATP synthase in itsmembrane. This will not only be an efficient wayof energy generation but also explain theconsumption of oxygen by cancerous cells.However, this leads to the question whether theelectron transport chain is intact and functionalin cancerous cell mitochondria or not? Vitalmitochondrial assays show that ETC enzymesare not only functional but have increased activity(13). Analysis of Oncomine database (44), furtherestablishes increase in expression of variousETC enzyme coding genes (Figure 2). Here,most notable is that almost all genes ofmitochondrial ATP synthase are up regulated in


Fig. 2. Expression of four ATP synthase subunits(i.ATP5J2, ii. ATP5H, iii. ATP5G1 and iv. ATP5I) indifferent breast cancer and stromal tissues A. innormal tissue and 11 different breast cancer types.0. normal (144) 1. Benign Breast Neoplasm (3) 2.Breast Carcinoma (14) 3. Breast Phyllodes Tumor(5) 4. Ductal Breast Carcinoma in Situ (10) 5. InvasiveBreast Carcinoma (21) 6. Invasive Ductal BreastCarcinoma (1,556) 7. Invasive Ductal and InvasiveLobular Breast Carcinoma (90) 8. Invasive LobularBreast Carcinoma (148) 9. Medullary BreastCarcinoma (32) 10. Mucinous Breast Carcinoma (46)11. Tubular Breast Carcinoma (67). Numbers in theparenthesis indicates number of samples analyzed.All the different breast cancer types show an increasein expression of ATP synthase subunits. B 1. Normaland 2. Stromal tissue.


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cancer cell (45). However, in stromal tissue mostof the genes coding for ATP synthase subunitsare down regulated which are an indication ofnonfunctional OXPHOS in stromal cells. Hence,in the light of facts that cancerous cells cansynthesize NADH and have high levels offunctional ATP synthase enzymes compared tonormal cells, it is irresistible to postulate thatcancerous cells utilize the efficient way of ATPsynthesis (OXPHOS) in addition to the aerobicglycolysis.

Concluding remarks : Altered mitochondrialmetabolism in cancerous cells has acquiredprofuse interest among oncologists worldwide;primarily to target the up-regulated pathways forthe development of anticancer drugs. Amongthese, PKM2, glutamine metabolism andtransport are being pursued to design and testspecific inhibitors. It is evident that inhibition ofany single enzyme cannot result in collapse ofcomplete pathway as subsequent steps getcompleted through alternative carbon source/s.Further, various metabolic rearrangements seemto fulfill the requirements of continuously dividingcancer cells rather than a cause of cancer.Hence, a cancerous cell already using multiplecarbon sources and a number of interlinkedpathways at its disposal, may further rearrangeits mitochondrial metabolic pathway targetedthrough a drug. In this background, it is necessaryto understand the site of truncation of TCA cycleand its complementary available pathways assimultaneous targeting of these would be aneffective therapeutic approach. Further, theimplication of breakdown of cancerous cellfueling from surrounding microenvironment indevelopment of effective therapeuticinterventions cannot be ignored.

Acknowledgements:Financial assistance from Department of

Biotechnology (DBT), Ministry of Science andTechnology, Government of India to carry out thisresearch is duly acknowledged.

References1. Vander Heiden, M.G., Cantley, L.C. and

Thompson, C.B. (2009). Understanding the

Warburg effect: the metabolic requirementsof cell proliferation, Science, 324: 1029-1033.

2. Boellaard, R., O'Doherty, M., Weber, W.,Mottaghy, F., Lonsdale, M., Stroobants,S., Oyen, W.G., Kotzerke, J., Hoekstra,O., Pruim, J., Marsden, P., Tatsch, K.,Hoekstra, C., Visser, E., Arends, B.,Verzijlbergen, F., Zijlstra, J., Comans, E.I.,Lammertsma, A., Paans, A., Willemsen,A., Beyer, T., Bockisch, A., Schaefer-Prokop, C., Delbeke, D., Baum, R., Chiti,A. and Krause, B. (2010). FDG PET andPET/CT: EANM procedure guidelines fortumour PET imaging: version 1.0, Eur. J.Nucl. Med. Mol. Imaging, 37: 181-200.

3. Gambhir, S.S. (2002). Molecular imagingof cancer with positron emissiontomography, Nat Rev Cancer, 2: 683-693.

4. Warburg, O. (1924). Über den Stoffwechselder Carcinomzelle., Naturwissenschaften,12: 1132-1137.

5. Warburg, O. (1956). On respiratory impair-ment in cancer cells, Science, 124: 269-270.

6. Koppenol, W.H., Bounds, P.L. and Dang,C.V. (2011). Otto Warburg's contributionsto current concepts of cancer metabolism,Nat Rev Cancer, 11: 325-337.

7. Ayyasamy, V., Owens, K.M., Desouki,M.M., Liang, P., Bakin, A., Thangaraj, K.,Buchsbaum, D.J., LoBuglio, A.F. andSingh, K.K. (2011). Cellular Model ofWarburg Effect Identifies Tumor PromotingFunction of UCP2 in Breast Cancer and ItsSuppression by Genipin, PLoS ONE, 6:e24792.

8. Vaishnavi, S.N., Vlassenko, A.G., Rundle,M.M., Snyder, A.Z., Mintun, M.A. andRaichle, M.E. (2010). Regional aerobicglycolysis in the human brain, Proc NatlAcad Sci USA, 107: 17757-17762.

9. Paul, R.J., Bauer, M. and Pease, W.(1979). Vascular smooth muscle: aerobic

Vikrant et al


436

glycolysis linked to sodium and potassiumtransport processes, Science, 206: 1414-1416.

10. Reitzer, L.J., Wice, B.M. and Kennell, D.(1979). Evidence that glutamine, not sugar,is the major energy source for culturedHeLa cells, J Biol Chem, 254: 2669-2676.

11. Fernandes, L.C., Marques-da-Costa, M.M.and Curi, R. (1994). Metabolism of glucose,glutamine and pyruvate in lymphocytesfrom Walker 256 tumor-bearing rats, BrazJ Med Biol Res, 27: 2539-2543.

12. Shlomi, T., Benyamini, T., Gottlieb, E.,Sharan, R. and Ruppin, E. (2011). Genome-Scale Metabolic Modeling Elucidates theRole of Proliferative Adaptation in Causingthe Warburg Effect, PLoS Comput Biol, 7:e1002018.

13. Sotgia, F., Whitaker-Menezes, D.,Martinez-Outschoorn, U.E., Flomenberg,N., Birbe, R.C., Witkiewicz, A.K., Howell,A., Philp, N.J., Pestell, R.G. and Lisanti,M.P. (2012). Mitochondrial metabolism incancer metastasis: visualizing tumor cellmitochondria and the "reverse Warburgeffect" in positive lymph node tissue, CellCycle, 11: 1445-1454.

14. Martinez-Outschoorn, U.E., Lin, Z.,Trimmer, C., Flomenberg, N., Wang, C.,Pavlides, S., Pestell, R.G., Howell, A.,Sotgia, F. and Lisanti, M.P. (2011). Cancercells metabolically "fertilize" the tumormicroenvironment with hydrogen peroxide,driving the Warburg effect: implications forPET imaging of human tumors, Cell Cycle,10: 2504-2520.

15. Whitaker-Menezes, D., Martinez-Outschoorn, U.E., Lin, Z., Ertel, A.,Flomenberg, N., Witkiewicz, A.K., Birbe,R.C., Howell, A., Pavlides, S., Gandara,R., Pestell, R.G., Sotgia, F., Philp, N.J.and Lisanti, M.P. (2011). Evidence for astromal-epithelial "lactate shuttle" in humantumors: MCT4 is a marker of oxidative

stress in cancer-associated fibroblasts,Cell Cycle, 10: 1772-1783.

16. Martinez-Outschoorn, U.E., Pavlides, S.,Howell, A., Pestell, R.G., Tanowitz, H.B.,Sotgia, F. and Lisanti, M.P. (2011). Stromal-epithelial metabolic coupling in cancer:integrating autophagy and metabolism inthe tumor microenvironment, Int J BiochemCell Biol, 43: 1045-1051.

17. Pavlides, S., Tsirigos, A., Vera, I.,Flomenberg, N., Frank, P.G., Casimiro,M.C., Wang, C., Pestell, R.G., Martinez-Outschoorn, U.E., Howell, A., Sotgia, F.and Lisanti, M.P. (2010). Transcriptionalevidence for the "Reverse Warburg Effect"in human breast cancer tumor stroma andmetastasis: similarities with oxidativestress, inflammation, Alzheimer's disease,and "Neuron-Glia Metabolic Coupling",Aging (Albany NY), 2: 185-199.

18. DeBerardinis, R.J., Mancuso, A., Daikhin,E., Nissim, I., Yudkoff, M., Wehrli, S. andThompson, C.B. (2007). Beyond aerobicglycolysis: transformed cells can engage inglutamine metabolism that exceeds therequirement for protein and nucleotidesynthesis, Proc Natl Acad Sci U S A, 104:19345-19350.

19. Desideri, E., Vegliante, R. and Ciriolo, M.R.(2014). Mitochondrial dysfunctions incancer: Genetic defects and oncogenicsignaling impinging on TCA cycle activity,Cancer letters, PMID: 24614286.

20. Zheng, J. (2012). Energy metabolism ofcancer: Glycolysis versus oxidativephosphorylation (Review), Oncol Lett, 4:1151-1157.

21. Shuch, B., Linehan, W.M. and Srinivasan,R. (2013). Aerobic glycolysis: a novel targetin kidney cancer, Expert Rev AnticancerTher, 13: 711-719.

22. Singleterry, J., Sreedhar, A. and Zhao, Y.(2014). Components of cancer metabolism



437

and therapeutic interventions,Mitochondrion, 17: 50-55.

23. Filipp, F.V., Ratnikov, B., De Ingeniis, J.,Smith, J.W., Osterman, A.L. and Scott,D.A. (2012). Glutamine-fueledmitochondrial metabolism is decoupledfrom glycolysis in melanoma, Pigment CellMelanoma Res, 25: 732-739.

24. Icard, P. and Lincet, H. (2012). A global viewof the biochemical pathways involved in theregulation of the metabolism of cancer cells,Biochimica et Biophysica Acta (BBA) -Reviews on Cancer, 1826: 423-433.

25. Raimundo, N., Baysal, B.E. and Shadel,G.S. (2011). Revisiting the TCA cycle:signaling to tumor formation, Trends MolMed, 17: 641-649.

26. Wallace, D.C. (2012). Mitochondria andcancer, Nat Rev Cancer, 12: 685-698.

27. Lehninger, A., Nelson, D.L. and Cox, M.M.(2008). Lehninger Principles ofBiochemistry, W.H. Freeman & Co., NewYork, USA.

28. Icard, P., Poulain, L. and Lincet, H. (2012).Understanding the central role of citrate inthe metabolism of cancer cells, Biochimicaet Biophysica Acta (BBA) - Reviews onCancer, 1825: 111-116.

29. Wong, N., De Melo, J. and Tang, D. (2013).PKM2, a Central Point of Regulation inCancer Metabolism, Int J Biochem CellBiol, 2013: 11.

30. Christofk, H.R., Vander Heiden, M.G.,Harris, M.H., Ramanathan, A., Gerszten,R.E., Wei, R., Fleming, M.D., Schreiber,S.L. and Cantley, L.C. (2008). The M2 spliceisoform of pyruvate kinase is important forcancer metabolism and tumour growth,Nature, 452: 230-233.

31. Chaneton, B., Hillmann, P., Zheng, L.,Martin, A.C.L., Maddocks, O.D.K.,Chokkathukalam, A., Coyle, J.E.,

Jankevics, A., Holding, F.P., Vousden,K.H., Frezza, C., O/'Reilly, M. and Gottlieb,E. (2012). Serine is a natural ligand andallosteric activator of pyruvate kinase M2,Nature, 491: 458-462.

32. Wise, D.R., Ward, P.S., Shay, J.E.S.,Cross, J.R., Gruber, J.J., Sachdeva, U.M.,Platt, J.M., DeMatteo, R.G., Simon, M.C.and Thompson, C.B. (2011). Hypoxiapromotes isocitrate dehydrogenase-dependent carboxylation of a-ketoglutarateto citrate to support cell growth and viability,Proc Natl Acad Sci, 108: 19611-19616.

33. Gardner, P.R., Raineri, I., Epstein, L.B.and White, C.W. (1995). Superoxide radicaland iron modulate aconitase activity inmammalian cells, J Biol Chem, 270:13399-13405.

34. Waris, G. and Ahsan, H. (2006). Reactiveoxygen species: role in the developmentof cancer and various chronic conditions,J Carcinog, 5: 14.

35. Hinder, L.M., Vincent, A.M., Burant, C.F.,Pennathur, S. and Feldman, E.L. (2012).Bioenergetics in diabetic neuropathy: whatwe need to know, J Peripher Nerv Syst,17: 10-14.

36. Gupta, K.J., Shah, J.K., Brotman, Y.,Jahnke, K., Willmitzer, L., Kaiser, W.M.,Bauwe, H. and Igamberdiev, A.U. (2012).Inhibition of aconitase by nitric oxide leadsto induction of the alternative oxidase andto a shift of metabolism towardsbiosynthesis of amino acids, J Exp Bot,63: 1773-1784.

37. Yen, K.E. and Schenkein, D.P. (2012).Cancer- associated isocitrate dehydrog-enase mutations, Oncologist, 17: 5-8.

38. Leonardi, R., Subramanian, C., Jackowski,S. and Rock, C.O. (2012). Cancer-associated Isocitrate DehydrogenaseMutations Inactivate NADPH-dependentReductive Carboxylation, J Biol Chem,287: 14615-14620.

Vikrant et al


438

39. Kloosterhof, N.K., Bralten, L.B., Dubbink,H.J., French, P.J. and van den Bent, M.J.(2011). Isocitrate dehydrogenase-1mutations: a fundamentally newunderstanding of diffuse glioma?, LancetOncol, 12: 83-91.

40. Reitman, Z.J. and Yan, H. (2012). IsocitrateDehydrogenase 1 and 2 Mutations inCancer: Alterations at a Crossroads ofCellular Metabolism, J Natl Cancer Inst,102: 932-941.

41. Krell, D., Assoku, M., Galloway, M.,Mulholland, P., Tomlinson, I. and Bardella,C. (2011). Screen for IDH1, IDH2, IDH3,D2HGDH and L2HGDH mutations inglioblastoma, PLoS One, 6: e19868.

42. King, A., M.A., S. and Gottlieb, E. (2006).Succinate dehydrogenase and fumaratehydratase: linking mitochondrial dysfunctionand cancer, Oncogene, 25: 4675-4682.

43. Gomes, L.C., Benedetto, G.D. andScorrano, L. (2011). During autophagymitochondria elongate, are spared from

degradation and sustain cell viability, NatCell Biol, 13: 589-598.

44. Rhodes, D.R., Kalyana-Sundaram, S.,Mahavisno, V., Varambally, R., Yu, J.,Briggs, B.B., Barrette, T.R., Anstet, M.J.,Kincead-Beal, C., Kulkarni, P., Varambally,S., Ghosh, D. and Chinnaiyan, A.M. (2007).Oncomine 3.0: genes, pathways, andnetworks in a collection of 18,000 cancergene expression profiles, Neoplasia, 9:166-180.

45. Curtis, C., Shah, S.P., Chin, S.F.,Turashvili, G., Rueda, O.M., Dunning, M.J.,Speed, D., Lynch, A.G., Samarajiwa, S.,Yuan, Y., Graf, S., Ha, G., Haffari, G.,Bashashati, A., Russell, R., McKinney, S.,Langerod, A., Green, A., Provenzano, E.,Wishart, G., Pinder, S., Watson, P.,Markowetz, F., Murphy, L., Ellis, I.,Purushotham, A., Borresen-Dale, A.L.,Brenton, J.D., Tavare, S., Caldas, C. andAparicio, S. (2012). The genomic andtranscriptomic architecture of 2,000 breasttumours reveals novel subgroups, Nature,486: 346-352.


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Role of TCA cycle Truncation in Cancer Cell Energeticsabap.co.in/sites/default/files/Paper-11_17.pdfThe question arises, how TCA cycle gets truncated in a cancerous cell, which has